Feingold et al. (1998) reported the use of ultrasound in third-trimester diagnosis of NPS. While ultrasound has the advantage of being noninvasive, the usefulness of third-trimester diagnosis is limited. McIntosh et al. (1999) ... - Prenatal Diagnosis Feingold et al. (1998) reported the use of ultrasound in third-trimester diagnosis of NPS. While ultrasound has the advantage of being noninvasive, the usefulness of third-trimester diagnosis is limited. McIntosh et al. (1999) used 5 DNA markers flanking the LMX1B locus to demonstrate that a fetus was affected. The pregnancy was terminated at 15 weeks. Feingold et al. (1998) considered prenatal diagnosis of NPS worthwhile because of the substantial risk for kidney disease and other associated malformations. In fact, less than 10% of the patients will develop renal failure, and the overall risk of having a renal disease is probably less than 25% (Looij et al., 1988). Most NPS families inquire about prenatal diagnosis only in the hope that severity can be predicted. It is in this regard that ultrasound may be of use in detecting early signs of severe renal damage, since there is no correlation between the LMX1B mutation and the presence of kidney disease, or overall NPS severity (McIntosh et al., 1998).
Dysplasia of the nails and absent or hypoplastic patellae are the cardinal features but others are iliac horns, abnormality of the elbows interfering with pronation and supination, and in some cases nephropathy. Nephropathy was an associated abnormality in ... Dysplasia of the nails and absent or hypoplastic patellae are the cardinal features but others are iliac horns, abnormality of the elbows interfering with pronation and supination, and in some cases nephropathy. Nephropathy was an associated abnormality in the family of Hawkins and Smith (1950). The renal change resembles glomerulonephritis. It is relatively benign although fatality at a young age from this complication has been described (Leahy, 1966). The renal disorder in the case of Simila et al. (1970) took the appearance of congenital nephrosis; 8 persons in the family had nail-patella syndrome, of whom 5 also had renal disease. The seeming familial aggregation of the renal complications suggested 2 separate genes, one for a nephropathic form and one for a nonnephropathic form. They might be allelic since no heterogeneity has been detected in the linkage with the ABO locus. As demonstrated by electron microscopy by Morita et al. (1973), among others, many collagen fibrils are present in the thickened basement membranes and in mesangial matrix of otherwise normal glomeruli. Abnormalities of collagen at this site have also been demonstrated in Alport syndrome (104200). Both of these conditions may be special forms of heritable disorders of connective tissue. Gilula and Kantor (1975) found colon cancer in association with the nail-patella syndrome. Sabnis et al. (1980) reported 3 patients with collagenation of glomerular basement membrane like that of the nail-patella syndrome. However, typical bone and nail changes were said to be absent. It is not clear how thoroughly the changes were sought or whether minor changes were present. An 8-year-old boy, son of first-cousin Palestinian Arabs, presented with the nephrotic syndrome. A sister and brother had died of renal disease at ages 6.5 and 9 years, respectively. A 13-year-old girl presented with recurrent urinary tract infections, proteinuria, and edema. No family information was provided. During evaluation of aortic regurgitation, a 27-year-old asymptomatic woman was noted to have proteinuria and renal insufficiency. A sister had undergone renal transplant (diagnosis unknown) and a brother had nephritis. The father's autopsy report stated 'severe interstitial nephritis and hypernephroma.' Questions include: (1) Do these cases represent variable expression of the classic nail-patella gene? (2) Is there a genetic form of glomerular basement membrane collagenosis that lacks the bone and nail involvement of the nail-patella syndrome, and is, perhaps, in light of case 1, inherited as an autosomal recessive? The range of variability of manifestation in a large series of cases ascertained through family studies has not, to my knowledge, been determined (VAM). The Goodpasture antigen, an autoantibody, comprises the NC1 domain of the alpha-3 chain of type IV collagen (see 120070). The occurrence of Goodpasture syndrome (233450) in a patient with NPS (Curtis et al., 1976) may be more than coincidence. This condition is sometimes called Fong disease for the physician who discovered it (Fong, 1946) in a patient on whom he performed intravenous pyelography while investigating hypertension and albuminuria related to pregnancy. No similar abnormality had been seen by many persons who reviewed the patient's films. No comments were made concerning nail dysplasia or absence of patellae. The name of Turner (1933) is associated with the disorder because of his description of 2 extensively affected families. (The designation Turner syndrome, however, leads to confusion with the XO syndrome.) He described the absence of the patellas and the inability to extend the elbows completely, as well as nail dysplasia. He also showed an x-ray of the pelvis which demonstrated the iliac horns clearly, but he made no reference to this finding in either the legend to the figure or in the text. Aschner (1934) reported that in a study on the genetics of the human skeletal system, she had found in the literature 8 families in which defect or hypoplasia of the patella was inherited through several generations with 'a hereditary defect of the thumbnails in all the affected members' of 3 of the families. Citing her mentor Julius Bauer as the authority, Aschner (1934) suggested that the association of nail dysplasia and absence of the patella was the consequence of close linkage of 2 mutant genes. She was sharply critical of the interpretation given by Oesterreicher (1930), who described affected members in 5 generations and interpreted the association as representing 'polyphenia' (which we would call pleiotropy, or pleiotropism). Aschner (1934) wrote: 'It is rather curious, therefore, that even Oesterreicher, who is well acquainted with the related literature, accepts the hypothesis of polyphenia. In my opinion this may be understood by the fact that this author, a neurologist, did not feel sufficiently secure in genetics to form an opinion of his own in regard to the genotypic connections of the observed symptoms. He therefore sought the advice of Paula Hertwig, the biologist. Hertwig, on the other hand, was naturally not familiar enough with the clinical facts, which would make a polyphenia impossible.' Both iliac horns and renal dysplasia were clearly identified as features of this syndrome by Hawkins and Smith (1950). The deformity of the pelvis characteristic of trisomy 8 suggests somewhat the presence of iliac horns but the appearance is quite different from that in the nail-patella syndrome (Giedion, 1990). Taguchi et al. (1988) demonstrated that characteristic ultrastructural changes in the glomerulus can be present even in patients without apparent clinical renal involvement. They reported a patient observed for 3 years, between ages 8 and 11. In a patient who had proteinuria before the age of 2 years, Browning et al. (1988) found characteristic changes in the glomeruli at age 27 months. Strong immunofluorescent staining, particularly for IgM, raised the possibility of superimposed immune complex disease. Richieri-Costa (1991) reported on 4 affected persons in a 3-generation Brazilian family with NPS. Three affected individuals had antecubital pterygium, 2 had proteinuria, and 1 had cleft lip and palate. Rizzo et al. (1993) described an Italian family in which bilateral antecubital pterygia, labeled arthrogryposis, was the presenting sign. Renal involvement was also severe in this family. From study of a large family with 30 patients with NPS (which the authors referred to as HOOD, hereditary osteoonychodysplasia), Looij et al. (1988) concluded that a person with NPS has a risk of about 1 in 4 of having a child with NPS nephropathy and a risk of about 1 in 10 of having a child in whom renal failure will develop. (It should be noted that they calculated their risk figures as a percentage in the article, i.e., 24% for the first risk, but stated the risk as a ratio, i.e., 1:4 in the abstract; these are not the same.) In the kidneys of an 18-week spontaneously aborted fetus of a mother with NPS, Drut et al. (1992) found changes which they suggested might be the basis of prenatal diagnosis by intrauterine kidney biopsy. Sweeney et al. (2003) reviewed the phenotype of NPS by comparing the results of their study of 123 British patients with previously published studies. They suggested that neurologic and vasomotor symptoms are also part of the NPS phenotype. They found reports of neurologic symptoms in 28 of 110 patients: intermittent episodes of numbness and tingling and sometimes burning sensations in the hands and sometimes the feet, with no obvious precipitant. Distribution was in a 'glove and stocking' pattern. A 6% prevalence of epilepsy was found in the NPS study population, as contrasted with a lifetime prevalence of epilepsy in the United Kingdom of 0.4%. The neurologic symptoms were considered particularly interesting in light of the role of Lmx1b in neuronal migration in the mouse and in the developing brain. Vasomotor problems consisted of poor peripheral circulation, with very cold hands and feet, even in warm weather, and in some patients a specific diagnosis of Raynaud phenomenon. The prevalences of glaucoma and ocular hypertension were 9.6% and 7.2%, respectively. Lester sign, which consists of a zone of darker pigmentation of roughly cloverleaf or flower shape around the central part of the iris that is most pronounced in blue eyes, was observed in 54% of the patients in this study, usually bilaterally. Lester sign was no more frequent among those with glaucoma or ocular hypertension than in those without. Sweeney et al. (2003) stated that it is widely accepted that the iris configuration characteristic of Lester sign is not pathognomonic of NPS and may be seen in the general population, although at considerably lower frequency. The stellate iris that is commonly seen in Williams syndrome (194050) also is seen in the general population, but at a much lower frequency. To examine bone mass and the prevalence of fragility fractures in patients with nail-patella syndrome, Towers et al. (2005) assessed bone mineral density (BMD) of the spine and hip in 31 adults and 12 children with mutation-confirmed NPS and 60 healthy age- and gender-matched adult controls. For the adults with NPS, BMD was 11 to 20% lower at the hip sites (P less than or equal to 0.001) and 8% lower at the spine (P less than 0.05) than that of controls. Towers et al. (2005) concluded that adults with NPS have a BMD that is 8 to 20% lower than controls, which is associated with an increase in the prevalence of fractures and scoliosis.
Bongers et al. (2005) performed LMX1B mutation analysis and comprehensive examinations in 106 subjects from 32 NPS families and found that individuals with an LMXB1 mutation located in the homeodomain showed significantly more frequent and higher values of ... Bongers et al. (2005) performed LMX1B mutation analysis and comprehensive examinations in 106 subjects from 32 NPS families and found that individuals with an LMXB1 mutation located in the homeodomain showed significantly more frequent and higher values of proteinuria than subjects with mutations in the LIM domains. No clear genotype-phenotype association was apparent for extrarenal manifestations.
Renwick (1956) found evidence that the expression of this autosomal dominant disorder, nail-patella syndrome, is modified by variation in the alleles on the 'normal' chromosome. The variants of the normal allele are known as isoalleles. Evidence that they ... Renwick (1956) found evidence that the expression of this autosomal dominant disorder, nail-patella syndrome, is modified by variation in the alleles on the 'normal' chromosome. The variants of the normal allele are known as isoalleles. Evidence that they affect in trans the expression of the mutant allele on the other chromosome comes from the fact that the correlation in characteristics of the disorder, e.g., severity by some measure, between sibs is greater than the correlation between parents and offspring. Using the nail defect and the patellar size as indices of severity, Renwick (1956) found parent-child correlations of approximately zero and sib-sib correlations of approximately one-half. Stern (1960) quoted Lionel Penrose who pointed out the likely operation of isoalleles in myotonic dystrophy (Penrose, 1948): the affected parent might be homozygous for an isoallele that favored reduced expression of the heterozygous mutation; let us symbolize the genotype d1d1. All affected children would have the d1 gene in cis with the mutation and the other chromosome carry the D1 allele making for increased expression of the mutation. Since all affected children might be heterozygous for the modifier change, the correlation between sibs should be much higher than that between affected parent and affected offspring. Dunston et al. (2005) found no support for a role of the wildtype allele in modifying the phenotype of the nail-patella syndrome. Earlier work by Renwick (1956), subsequently expanded by Renwick and Izatt (1965), identified a correlation between affected sibs of approximately 0.50 for both nail and patellar dysplasia, in the absence of a correlation between the 2 aspects of the phenotype, or between affected parent-child pairs. The results were as expected if the modifier(s) is an allele at the NPS locus, and inherited from the unaffected parent, i.e., as an isoallele. On the other hand, Dunston et al. (2005) demonstrated association between the haplotype of the mutant allele and the variability in the nail score (p = 0.024). The LIM-homeodomain protein Lmx1b plays a central role in dorsal/ventral patterning of the vertebrate limb. Targeted disruption of Lmx1b results in skeletal defects, including hypoplastic nails, absent patellae, and a unique form of renal dysplasia (Chen et al., 1998). Dreyer et al. (1998) showed that the LMX1B gene maps to 9q in the same region as the NPS locus by fluorescence in situ hybridization. Furthermore, they demonstrated that 3 unrelated NPS patients carried de novo heterozygous mutations in this gene. Functional studies showed that one of these mutations disrupted sequence-specific DNA binding, while the other 2 mutations resulted in premature termination of translation. These were the first described mutations in a LIM-homeodomain protein that accounted for an inherited form of abnormal skeletal patterning and renal failure. Lichter et al. (1997) and McIntosh et al. (1997) described cosegregation of primary open angle glaucoma (POAG; 137760) and NPS. In 2 families, Lichter et al. (1997) found linkage results indicating that the cosegregation was the result of a pleiotropic effect of the NPS1 gene at 9q34. In a further study of 29 additional families, 28 of them ascertained on the basis of NPS, glaucoma was present in 9 (31%). In 1 family an individual with open angle glaucoma but no nail-patella syndrome was found; there may have been another explanation for the open angle glaucoma. That the glaucoma is a genuine pleiotropic effect of the NPS1 gene is supported by the finding of anterior segment ocular abnormalities in mice with targeted disruption of the Lmx1b gene (McIntosh, 1998). Vollrath et al. (1998) demonstrated mutations in the LMX1B gene in 4 families with combined NPS and open angle glaucoma. Using multiplex ligation-probe amplification (MLPA) analysis, Bongers et al. (2008) identified a heterozygous deletion of the entire LMX1B gene (602575.0013) in 2 unrelated patients with nail-patella syndrome. The phenotype was similar to other reported cases with point or truncating mutations. The findings confirmed that haploinsufficiency of LMX1B is the pathogenic mechanism in nail-patella syndrome.
No clinical diagnostic criteria for nail-patella syndrome (NPS) exist; however, the combination of clinical features seen in this condition is characteristic. The classic clinical tetrad comprises: ...
DiagnosisClinical DiagnosisNo clinical diagnostic criteria for nail-patella syndrome (NPS) exist; however, the combination of clinical features seen in this condition is characteristic. The classic clinical tetrad comprises: Nail changes. Nail changes are the most constant feature of NPS (98%). Nails may be absent, hypoplastic, or dystrophic; ridged longitudinally or horizontally; pitted; discolored; separated into two halves by a longitudinal cleft or ridge of skin; and thin or (less often) thickened. The nail changes may be limited to triangular lunules (or lunulae), a characteristic feature of NPS (Figure 1). Nail changes may be observed at birth and are most often bilateral and symmetrical. The thumbnails are the most severely affected; the severity of the nail changes tends to decrease from the index finger toward the little finger. Each individual nail is usually more severely affected on its ulnar side. Dysplasia of the toenails is usually less marked and less frequent than that of the fingernails; if the toenails are involved, it is often the little toenail that is affected. Knee involvement. The patellae may be small, irregularly shaped, or absent. Patella involvement may be asymmetrical. Recurrent subluxation or dislocation of the patella is common in NPS and may be associated with poor development of the vastus medialis muscle. The displacement of the patella is lateral and superior; the hypoplastic patella is often located laterally and superiorly even when not actually dislocated. There may be prominent medial femoral condyles, hypoplastic lateral femoral condyles, and prominent tibial tuberosities. These changes together with a hypoplastic or absent patella give the knee joint a flattened profile. Symptoms of knee involvement were apparent in 74% of cases in one study [Sweeney et al 2003]. Elbow involvement. Elbow abnormalities may include limitation of extension, pronation, and supination; cubitus valgus; and antecubital pterygia. Elbow abnormalities may be asymmetrical. Typical radiologic findings include dysplasia of the radial head, hypoplasia of the lateral epicondyle and capitellum, and prominence of the medial epicondyle. These abnormalities may result in dislocation of the radial head, usually posteriorly. Approximately 70% of individuals with NPS exhibit some degree of elbow involvement [Sweeney et al 2003]. Iliac horns. Iliac horns are bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis. They are present in about 70% of individuals with NPS and are considered pathognomonic of NPS [Sweeney et al 2003]. Pelvic x-ray is usually necessary for their detection (Figure 2). Although large horns may be palpable, they are asymptomatic. Iliac horns may be seen on third-trimester ultrasound scanning [Feingold et al 1998], on x-ray at birth, and by bone scan [Goshen et al 2000]. In children, iliac horns may have an epiphysis at the apex. FigureFigure 1. Typical presentation of thumb nails (a) and finger nails (b) in NPS. The arrow points to the index finger. Note decrease in severity of nail involvement from 2nd to 5th finger and lack of creases over the distal interphalangeal joints. FigureFigure 2. Iliac horns (arrows) in an individual with NPS Additional findings are not really considered as part of the diagnosis but the main clinical features should be looked for in an individual presenting with glaucoma or proteinuria as a primary feature.TestingCytogenetic testing. Chromosomal translocations disrupting the gene have also been reported [Silahtaroglu et al 1999] but represent a rare pathogenic mechanism. Molecular Genetic TestingGene. LMX1B is the only gene in which mutation is known to cause NPS. Clinical testing Sequence analysis. Sequence analysis of LMX1B exons 2 through 6 and their intronic junctions detects approximately 85% of LMX1B mutations. The other 15% of mutations presumably lie elsewhere in LMX1B [Clough et al 1999]. Deletion/duplication testing. It appears that about 5% of individuals with nail-patella syndrome have a deletion of a substantial part of LMX1B detected using Southern blot analysis [Dunston et al 2004; Author, personal observation]. FISH analysis. No studies have been published on the frequency of whole-gene deletions. Table 1. Summary of Molecular Genetic Testing Used in Nail-Patella SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityLMX1BSequence analysisSequence variants 2 exons 2 through 685% 3Clinical Deletion / duplication analysis 4Exonic or whole-gene deletions5%FISH analysisLarge deletionsUndetermined1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Proportion of affected individuals with mutations identified by sequence analysis of exons 2-6 [Clough et al 1999, Sweeney et al 2003]4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy Confirmation of the diagnosis in a proband may require molecular genetic testing if the phenotype is atypical or cytogenetic testing if signs and symptoms beyond the typical NPS phenotype are present. Prenatal diagnosis/preimplantation genetic diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in LMX1B.
The classic clinical tetrad of nail patella syndrome involves changes in the nails, knees, and elbows, and the presence of iliac horns (see Clinical Diagnosis). Many other features may be seen in NPS, and involvement of other body systems such as the kidneys and eyes is well documented [Sweeney et al 2003]. The clinical manifestations are extremely variable in both frequency and severity, with inter- and intrafamilial variability. Individuals may be severely affected by one aspect of NPS but have much milder or no manifestations elsewhere. Males and females are affected equally. Although the diagnosis may be made at birth, it is common for families to remain undiagnosed for several generations despite having been seen by doctors from a variety of disciplines....
Natural HistoryThe classic clinical tetrad of nail patella syndrome involves changes in the nails, knees, and elbows, and the presence of iliac horns (see Clinical Diagnosis). Many other features may be seen in NPS, and involvement of other body systems such as the kidneys and eyes is well documented [Sweeney et al 2003]. The clinical manifestations are extremely variable in both frequency and severity, with inter- and intrafamilial variability. Individuals may be severely affected by one aspect of NPS but have much milder or no manifestations elsewhere. Males and females are affected equally. Although the diagnosis may be made at birth, it is common for families to remain undiagnosed for several generations despite having been seen by doctors from a variety of disciplines.Digital changes. In NPS, a reduction in flexion of the distal interphalangeal (DIP) joints is associated with loss of the creases in the skin overlying the dorsal surface of the DIP joints of the fingers. The gradient of severity is the same as seen in the nails; therefore, the index fingers are the most affected. Hyperextension of the proximal interphalangeal (PIP) joints with flexion of the DIP joints (resulting in "swan-necking") and fifth finger clinodactyly may be seen. Knee involvement. In addition to the previously mentioned patellar abnormalities, tight hamstring muscles may cause flexion contractures of the knees. There may also be osteochondritis dissecans, synovial plicae, and absence of the anterior cruciate ligament. Early degenerative arthritis is common. Symptoms associated with knee abnormalities in NPS include pain, instability, locking, clicking, patella dislocation, and inability to straighten the knee joint. Involvement of the ankles and feet. Talipes equinovarus, calcaneovarus, calcaneovalgus, equinovalgus, and hyperdorsiflexion of the foot may occur. Tight Achilles tendons are common, contributing to talipes equinovarus and to toe-walking. Pes planus is common. Spinal and chest wall problems. Back pain occurs in half of individuals with NPS. There may be an increased lumbar lordosis, scoliosis (usually mild), spondylolisthesis, spondylolysis, or pectus excavatum. Osteoporosis. Bone mineral density (BMD) is reduced by 8%-20% in the hips of individuals with NPS. An increased rate of fractures has also been reported.General appearance. A lean body habitus may be associated with NPS and affected individuals often have difficulty putting on weight (particularly muscle) despite adequate dietary intake and exercise. In particular, muscle mass in the upper arms and upper legs tends to be decreased. The tendency to be very lean is most evident in adolescents and young adults and becomes less apparent after middle age. Increased lumbar lordosis may make the buttocks appear prominent. The high forehead and hairline, particularly at the temples, resembles a receding male pattern hairline when seen in women. Renal involvement. Renal involvement occurs in 30%-50% of individuals with NPS; end-stage renal disease (ESRD) occurs in approximately 5% [Sweeney et al 2003]. The first sign of renal involvement is usually proteinuria, with or without hematuria. Proteinuria may present at any age from birth onwards and may be intermittent. Renal problems may present, or be exacerbated, during pregnancy. Once proteinuria is present, it may remit spontaneously, remain asymptomatic, or progress to nephrotic syndrome and occasionally to ESRD. Progression to renal failure may appear to occur rapidly or after many years of asymptomatic proteinuria. The factors responsible for this progression are yet to be identified. Nephritis may also occur in NPS. Ultrastructural (electron microscopic) renal abnormalities are the most specific histologic changes seen in NPS and include irregular thickening of the glomerular basement membrane with electron-lucent areas giving a mottled "moth-eaten" appearance, and the presence of collagen-like fibers within the basement membrane and the mesangial matrix. Ophthalmologic findings. Primary open-angle glaucoma and ocular hypertension occur at increased frequency in NPS and at a younger age than in the general population [Lichter et al 1997, Sweeney et al 2003]. Congenital and normal-tension glaucoma have been reported in individuals with NPS [Lichter et al 1997].Iris pigmentary changes (termed Lester's sign) consisting of a zone of darker pigmentation shaped like a cloverleaf or flower around the central part of the iris are seen frequently. Gastrointestinal involvement. One third of individuals with NPS have problems with constipation (often from birth) or irritable bowel syndrome [Sweeney et al 2003]. Neurologic problems. Many individuals with NPS exhibit reduced sensation to pain and temperature in the hands and feet, most likely because of the inability of Aδ and C fibers to connect with interneurons in the dorsal spinal cord [Dunston et al 2005]. Some affected individuals report intermittent numbness, tingling, and burning sensations in the hands and feet, with no obvious precipitant. Rarely, these symptoms may be secondary to local orthopedic problems or neurologic compromise from the spine or cervical ribs. In most cases, however, the paresthesia follows a glove and stocking pattern rather than the distribution of a particular dermatome or peripheral nerve. Epilepsy was reported in 6% of affected individuals in one large study [Sweeney et al 2003]. Vasomotor problems. Some individuals have symptoms of a poor peripheral circulation, such as very cold hands and feet, even in warm weather. Some may be diagnosed with Raynaud's phenomenon [Sweeney et al 2003]. Dental problems. Dental problems may include weak, crumbling teeth and thin dental enamel [Sweeney et al 2003].
Table 2. Differential Diagnoses of Nail-Patella Syndrome...
Differential DiagnosisTable 2. Differential Diagnoses of Nail-Patella SyndromeView in own windowSyndromeSimilaritiesDifferencesReferencesSmall patella syndrome (ischiopatellar dysplasia, coxo-podo-patellar syndrome, Scott-Taor syndrome)Small or absent patellae Recurrent patella dislocations Pelvic anomaliesDefective ossification at the ischiopubic junction Ischial hypoplasia Infra-acetabular "axe-cut" notch No nail changes No elbow changes No renal involvement No ocular involvement OMIM 147891, Bongers et al [2004] Patella aplasia-hypoplasia (PTLAH)Isolated aplasia OR Hypoplasia of the patella No nail changes No elbow changes No renal involvement No ocular involvement OMIM 168860Familial recurrent dislocation of the patellaFamilial tendency toward patella dislocation OMIM 169000Meier-Gorlin syndromeAbsent patellae Dislocation of the radial headMicrotia Markedly short stature Delayed bone age Characteristic facial appearance Autosomal recessive inheritance OMIM 224690Genitopatellar syndromeAbsent patellae Renal anomalies Flexion deformities of the knees and hips Club footHypoplasia of the ischia and iliac bones Genital anomalies Facial dysmorphism Microcephaly Intellectual disability Structural (multicystic kidneys or hydronephrosis) rather than functional abnormalities Renal manifestations OMIM 606170, Cormier-Daire et al [2000]DOOR syndrome Absent or poorly formed nailsLong thumbs and big toes, often with triphalangy Other fingers and toes short as the result of an absent or hypoplastic distal phalanx Bilateral ptosis Short broad nose with a broad nasal tip and large nostrils Structural renal tract abnormalities Cataracts Optic atrophy Dandy-Walker malformation Seizures Autosomal recessive inheritance OMIM 220500, Winter & Baraitser [2000] Trisomy 8 mosaicismAbsent or hypoplastic patellae Limited elbow supination Abnormal nails Significant learning difficulties Variable facial dysmorphism Camptodactyly and progressive joint restriction, usually of the fingers and toes Jones [1997] Coffin-Siris syndrome Absence or hypoplasia of the nails and patellae Elbow dislocation Nail hypoplasia, usually affecting the little finger nails Facial dysmorphism OMIM 135900, Winter & Baraitser [2000] RAPADILINO syndrome (see Rothmund-Thomson Syndrome, Genetically Related Disorders) Radial defects Absent or hypoplastic patellae Dislocated jointsCleft palate Facial dysmorphism Short stature Radial defects, including absent or hypoplastic thumbs and radii Autosomal recessive inheritance OMIM 266280, Winter & Baraitser [2000] Senior syndromeSmall nailsCharacteristic facial appearance Short stature Mild intellectual impairment OMIM 113477
To establish the extent of disease in an individual diagnosed with nail-patella syndrome (NPS), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with nail-patella syndrome (NPS), the following evaluations are recommended:Blood pressure measurement and urinalysis to screen for renal disease, plus a urine albumin:creatinine ratio on a first-morning urine. The latter is a more sensitive measure of renal disease than urinalysis as it corrects for urine concentration. If any abnormalities are detected, the individual should then be referred to a nephrologist. Screening for glaucoma as soon as a child is able to cooperate with the examination. The examination should include measurement of intraocular pressure, examination of the optic disc, and assessment of visual fields in order to detect normal pressure glaucoma. If any abnormalities are detected, individuals should be referred to an ophthalmologist. Any infant or young child found to have an abnormal or absent red reflex on eye examination by a primary care physician should be referred to an ophthalmologist immediately. History and physical examination to detect orthopedic problems History to identify gastrointestinal, neurologic, or vasomotor abnormalities Before surgery or intensive physiotherapy is performed for orthopedic complaints, investigation via MRI of possible bone/soft tissue abnormalities History and examination to detect dental anomalies Consideration of formal quantification of bone mineral density (BMD) via dual-energy x-ray absorptiometry (DEXA) as indicator of fracture propensity based on reported low BMD and increased fracture risk in NPS. DEXA norms are readily available in most clinical settings for adults and may be pursued in all young adults (>age 18 years) at least once. Pediatric DEXA norms are often less readily available, but may be obtained via local pediatric endocrinologist or machine manufacturer. No formal recommendations for DEXA scanning of pediatric patients exist at this time, but DEXA should be pursued if fractures or unexplained skeletal pain occurs with additional clinical evaluation.Treatment of ManifestationsHypertension and renal disease are treated as in the general population. When renal transplantation is necessary, results are usually favorable. ACE inhibitors are useful in slowing progression of proteinuria but their use should be monitored carefully in children. Orthopedic problems may be helped by analgesics, physiotherapy, splinting, bracing, or surgery. Because of the abnormal joint anatomy that may be present in patients with NPS, MRI of joints is important prior to surgery so that appropriate surgical treatment can be planned in advance.Treatment as in the general population for: Glaucoma ConstipationDental problems SurveillanceAnnual measurement of the following is appropriate:Measurement of blood pressure Urinalysis Urine albumin:creatinine ratio on a first-morning urine. If any abnormalities are detected, the individual should then be referred to a nephrologist. Screening for glaucoma from the time that a child is compliant with the examination Dental examination is indicated at least every six months. DEXA scanning frequency in adults is based on clinical symptoms, abnormalities detected on previous evaluations, and standard practice in peri-/post-menopausal females and older males. Agents/Circumstances to AvoidChronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided because of their detrimental effect on kidney function.Evaluation of Relatives at RiskEarly diagnosis of NPS in at-risk family members allows for ophthalmologic and renal screening – especially in individuals with mild-moderate skeletal involvement who may not otherwise come to clinical attention. Molecular genetic testing can be used if the disease-causing mutation in the family is known; otherwise, monitor renal findings (i.e., blood pressure, urinalysis, and urine albumin:creatinine ratio on a first-morning urine) and screen for glaucoma. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Nail-Patella Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDLMX1B9q33.3LIM homeobox transcription factor 1-betaLMX1B homepage - Mendelian genesLMX1BData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Nail-Patella Syndrome (View All in OMIM) View in own window 161200NAIL-PATELLA SYNDROME; NPS 602575LIM HOMEOBOX TRANSCRIPTION FACTOR 1, BETA; LMX1BNormal allelic variants. LMX1B comprises eight exons covering more than 90 kb, transcribed and spliced to an approximately 7-kb mRNA. LMX1B is a member of the LIM-homeodomain family. Alternative splicing of 21 bp at the 3' end of exon 7 has been observed; the biologic significance of this event remains to be determined. A series of single-nucleotide normal variants has been identified [Clough et al 1999]. Pathologic allelic variants. More than 130 mutations have been identified. Nonsense, frameshift, splice site, and missense mutations have all been reported, as well as deletions of part, or all, of the gene [Dunston et al 2004]. All amino acid substitutions that have been observed cause NPS [Dunston et al 2004]. Missense mutations are concentrated within the homeodomain and the residues in the LIM domains essential for maintaining the zinc finger structures. A series of recurrent mutations within the homeodomain accounts for approximately 30% of all LMX1B mutations [Clough et al 1999]. No mutations have been identified in the terminal third of the gene. Normal gene product. The predicted protein comprises 395 or 402 amino acids (depending on alternative splicing of 21 bp at the 3' end of exon 7). Abnormal gene product. NPS is the result of heterozygous loss-of-function mutations within the gene encoding the transcription factor. Because all types of mutations (including large deletions and translocations) result in the same phenotype [Dunston et al 2004], it is believed that NPS is the result of haploinsufficiency for LMX1B. There is no evidence that transcripts bearing nonsense or frameshift mutations escape nonsense-mediated mRNA decay and cause any dominant-negative effects on the normal gene product. Missense mutations within the homeodomain reduce or eliminate DNA binding [Dreyer et al 1998, McIntosh et al 1998, Dreyer et al 2000, Bongers et al 2002]. Missense mutations within the LIM domains are believed to affect the secondary structure of the zinc fingers [McIntosh et al 1998, Clough et al 1999].